Prevention of Graft-Versus-Host disease in mice using a suicide gene expressed in T-lymphocytes

Cohen, J.L.; Boyer, Olivier; Salomon, Benoı̂t L.; Onclercq, Rosine; Klatzmann, David

doi:10.1016/s0165-2478(97)86478-4

Cited by 16 publications

(21 citation statements)

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“…The dramatic complications of adverse graft-versus-host disease development call for gene therapeutic approaches to stably induce in the cells desired properties, such as suicide genes or inactivating molecules (Bonini et al, 1997;Cohen et al, 1997;Verzeletti et al, 1998;Introna et al, 2000;Lal et al, 2000;Garin et al, 2001;Tiberghien et al, 2001). So far, gene transfer in T lymphocytes has been largely limited to replicating cells because of the constraints given by the oncovectors used, which are generally derived from the Moloney murine leukemia virus (Kay et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

A Human Immunodeficiency Virus Type 1polGene-Derived Sequence (cPPT/CTS) Increases the Efficiency of Transduction of Human Nondividing Monocytes and T Lymphocytes by Lentiviral Vectors

et al. 2002

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We have investigated the capacity of two human immunodeficiency virus type 1-derived lentivectors, differing in the presence of a 118-bp pol fragment containing the cPPT/CTS element, to transduce human normal primary cells of different hematopoietic lineages. Infection of resting monocytes with a high multiplicity of infection (MOI > 10) revealed that the lentivirus carrying the pol fragment (cPPT) is effective, transducing 75% of cells compared with 36% for the no-cPPT vector. Even at low MOIs (< or =1) the cPPT vector still shows a better transduction efficiency than the no-cPPT vector. Moreover, transduction does not require dendritic cell differentiation. In contrast, infection of nonactivated T lymphocytes showed that both vectors, tested at high MOIs, can transduce a small, although measurable, percentage of cells (up to 10%), which may correspond to G(1a) "activated" cells as detected by simultaneous staining of DNA and RNA, in our cultures in the presence of medium alone. Furthermore, we show that the sole addition of interleukin 2 or interleukin 15 represents a full proliferative signal under our conditions and permits high transduction efficiency (up to 30% with the cPPT vector and 15% with the no-cPPT vector). Still higher transduction of T lymphocytes can be achieved after stimulation with phytohemagglutinin and interleukin 2 (up to 78% with the cPPT vector vs. 42% with the no-cPPT vector). Finally, both viruses do not transduce either resting or proliferating tonsillar B lymphocytes.

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Section: Discussionmentioning

confidence: 99%

A Human Immunodeficiency Virus Type 1polGene-Derived Sequence (cPPT/CTS) Increases the Efficiency of Transduction of Human Nondividing Monocytes and T Lymphocytes by Lentiviral Vectors

et al. 2002

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“…The development of an HSV-tk transgenic mouse has been described with expression of HSV-tk in the T cells (Cohen et al, 1997;Lake-Bullock et al, 1997). These HSV-tk T cells can easily be used to generate GvHD in an allogeneic BMT mouse model and subsequently to study the effect of GCV treatment (Cohen et al, 1997;Lake-Bullock et al, 1997;Contassot et al, 2000;Drobyski et al, 2001).…”

Section: Fig 10mentioning

confidence: 99%

“…These HSV-tk T cells can easily be used to generate GvHD in an allogeneic BMT mouse model and subsequently to study the effect of GCV treatment (Cohen et al, 1997;Lake-Bullock et al, 1997;Contassot et al, 2000;Drobyski et al, 2001). However, in these experimental animal models GvHD is induced with fresh, nonactivated T cells without including the effect of T cell activation, culture, and selection.…”

Section: Fig 10mentioning

confidence: 99%

“…Treatment with GCV when GvHD is developing will eliminate transduced donor T cells that are proliferating in response to alloantigens whereas the resting T cell population not involved in GvHD survives. The applicability of the method has been demonstrated in vitro and in vivo by several preclinical studies (Tiberghien et al, 1994;Cohen et al, 1997;Lake-Bullock et al, 1997;Drobyski et al, 2001;Kornblau et al, 2001) and the first clinical studies have been initiated (Bordignon et al, 1995;Tiberghien, 1997;Link et al, 1998). GCV-induced elimination of suicide gene-transduced donor T cells and abrogation of GvHD have indeed been demonstrated in patients (Bonini et al, 1997;Tiberghien et al, 2001).…”

Section: Introductionmentioning

confidence: 98%

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Reduced Graft-Versus-Host Disease-Inducing Capacity of T Cells After Activation, Culturing, and Magnetic Cell Sorting Selection in an Allogeneic Bone Marrow Transplantation Model in Rats

Weijtens¹,

Spronsen²,

Hagenbeek³

et al. 2002

Human Gene Therapy

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Graft-versus-host disease (GvHD), a major complication of allogeneic bone marrow transplantation, has been ascribed to mature T cells in the graft. Because T cells play an important role in engraftment of the bone marrow and decrease the probability of relapse of leukemia, a treatment strategy was developed to preserve the benefits of T cells in the graft and to control the severe complications of GvHD. This can be accomplished by the genetic modification of donor T cells with a suicide gene that allows their selective in vivo elimination and subsequently the abrogation of GvHD. For clinical benefit the alloreactivity of herpes simplex virus thymidine kinase (HSV-TK) gene-transduced T cells should be retained. Therefore, we investigated the influence of gene transduction and the selection procedure on T cells. We demonstrated that activation and culturing of T cells reduce their capacity to induce lethal GvHD in an allogeneic rat bone marrow transplantation model. Furthermore, positive immunomagnetic selection of gene-transduced T cells resulted in loss of the GvHD-inducing capacity of HSV-TK(+) T cells directly after MACS (magnetic cell sorting) selection; this loss could be recovered by a 1-day expansion of the selected T cells. No effect on alloreactivity was observed to be caused by the gene transduction procedure. Our study resulted in the development of an optimized culture and gene transduction protocol with preservation of T cell alloreactivity. Treatment of transplanted rats with ganciclovir resulted in a rapid reduction in the number of HSV-TK(+) T cells in the peripheral blood and in increased survival of the animals.

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“…Thus, this approach could allow the inclusion of T cells with their positive effects on engraftment, GVL, and immunologic function while providing an additional measure of protection from severe GVHD. There have been reports suggesting that this is feasible in murine models (Cohen et al, 1997;Contassot et al, 2000), and may prove advantageous in a clinical setting (Bonini et al, 1997;Tiberghien, 2001;Tiberghien et al, 2001). The successful implementation of this procedure requires the resolution of several obstacles.…”

Section: Introductionmentioning

confidence: 99%

Clinical-Scale Selection of Anti-CD3/CD28–Activated T Cells After Transduction with a Retroviral Vector Expressing Herpes Simplex Virus Thymidine Kinase and Truncated Nerve Growth Factor Receptor

et al. 2002

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Activation of T cells is necessary for efficient retroviral-mediated gene transfer. In addition, if the population of infused cells is to be limited to transduced cells, a means of positive selection is required. We describe a clinical scale procedure for activation of donor T cells with anti-CD3/CD28 beads followed by transduction with a retroviral construct expressing the herpes simplex virus thymidine kinase (HSV-tk) and human nerve growth factor receptor (NGFR). Optimization of transduction parameters was performed, testing the timing of transduction, centrifugation, and the use of serum. In large-scale experiments, 3-5 x 10(8) peripheral blood mononuclear cells (PBMC) were activated with anti-CD3/CD28 beads and expanded to day 13. Transduction was accomplished using MFG-TKiNG supernatant produced from the PG13 packaging line 48 hr after T-cell activation. The mean transduction frequency was 37.5% based on NGFR expression, and the mean expansion observed was 42.6-fold (mean final cell number 1.85 x 10(10)). A comparison of the ability of the Baxter Isolex 300i and the Miltenyi CliniMACS to perform purification of NGFR+ cells suggests that greater purity can be achieved with the CliniMACS device (67.4% vs. 97.7%), while the yield of transduced cells appears higher with the Isolex 300i (41.3% vs. 23.5%). We conclude that a strategy based on activation of human T cells with anti-CD3/CD28 beads can result in sufficient transduction, expansion, and purification based on NGFR expression for clinical trials.

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Prevention of Graft-Versus-Host disease in mice using a suicide gene expressed in T-lymphocytes

Cited by 16 publications

References 0 publications

A Human Immunodeficiency Virus Type 1polGene-Derived Sequence (cPPT/CTS) Increases the Efficiency of Transduction of Human Nondividing Monocytes and T Lymphocytes by Lentiviral Vectors

A Human Immunodeficiency Virus Type 1polGene-Derived Sequence (cPPT/CTS) Increases the Efficiency of Transduction of Human Nondividing Monocytes and T Lymphocytes by Lentiviral Vectors

Reduced Graft-Versus-Host Disease-Inducing Capacity of T Cells After Activation, Culturing, and Magnetic Cell Sorting Selection in an Allogeneic Bone Marrow Transplantation Model in Rats

Clinical-Scale Selection of Anti-CD3/CD28–Activated T Cells After Transduction with a Retroviral Vector Expressing Herpes Simplex Virus Thymidine Kinase and Truncated Nerve Growth Factor Receptor

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